The present invention relates to methods of diagnosing, treating, or ameliorating sexual dysfunction in female mammals, including methods of treating delayed vaginal engorgement, diminished vaginal lubrication, pain or discomfort with intercourse (dyspareunia), diminished vaginal sensation, diminished vaginal orgasm, diminished clitoral sensation or diminished clitoral orgasm, or of treating vaginal pain by stimulating peripheral pelvic nerve release of nitric oxide (NO). The treatment methods of the present invention include the improvement in a female of the physiological state associated with sexual activity including appropriate vaginal lubrication, vaginal sensation, vaginal orgasm, or clitoral sensation, but in whom one of the above-mentioned abnormal conditions may not be present.
Sexual response in mammals is mediated by a balanced interplay between the sympathetic and parasympathetic nervous systems. Vasocongestion, or erectile tumescence in both the male and female, is largely mediated by parasympathetic (cholinergic) outflow, whereas orgasm is predominantly sympathetic (adrenergic).
Sexuality in human females encompasses multiple components including physiological, psychological, social and emotional factors. However, the first phase of the female sexual response is mediated by a combination of vasocongestive and neuromuscular events which include increased clitoral length and diameter, as well as increased vaginal lubrication, wall engorgement and increased luminal diameter.
The clitoris is the homologue of the penis, arising from the embryological genital tubercle. As a result, the two organs have similar structural and arousal response mechanisms. The clitoris consists of a cylindrical, erectile organ composed of three parts: the outermost glans or head, the middle corpus or body, and the innermost crura. The body of the clitoris consists of paired corpora cavernosa of about 2.5 cm in length and lacks a corpus spongiosum. During sexual arousal, blood flow to the corpora cavernosa of the clitoris cause their enlargement and tumescence. The clitoris plays a major role during sexual activity in that it induces local autonomic and somatic reflexes causing vaginal vasocongestion, engorgement, and subsequent transduction, lubricating the introital canal making the sexual act easier, more comfortable, and more pleasurable.
Vaginal wall engorgement enables a process of plasma transduction to occur, allowing a flow through the epithelium and onto the vaginal surface. Plasma transduction results from the rising pressure in the vaginal capillary bed during the sexual arousal state. In addition, there is an increase in vaginal length and luminal diameter, especially in the distal ⅔ of the vaginal canal.
The vaginal canal is lubricated primarily from a transudate originating from the subepithelial vascular bed passively transported through the interepithelial spaces sometimes referred to as intercellular channels. Additional moistening during intercourse comes from secretion of the paired greater vestibular or Bartholin""s glands.
These events depend upon sufficient blood flow to these organs during sexual arousal, and a physiologic disorder which impairs this blood flow, resulting in female vasculogenic sexual dysfunction, can ultimately lead to or exacerbate a pre-existing psychological condition.
The arterial supply to the vagina is derived from an extensive network of branching vessels surrounding it from all sides. The anterior branch of the internal iliac artery continually bifurcates as it descends through the pelvis with a series of the newly generated vessel, each supplying the vagina to some degree. After giving off an obturator artery branch, the umbilical and the middle rectal arteries diverge off to supply a superior and inferior vesical artery, respectively. Between the umbilical and the mid-rectal branches there is generation of a uterine artery which further bifurcates to give the vaginal artery. The internal pudendal and accessory pudendal artery also sends a branch. Finally the common clitoral artery sends a branch to the vaginal muscularis.
The main arterial supply to the clitoris is from the ilio-hypogastric-pudendal arterial bed. The internal pudendal artery is the last anterior branch of the internal iliac artery. Distally, the internal pudendal artery traverses Alcock""s canal, a position of the obturator fascia and lies on the inner side in supposition to the ischio-pubic ramis. In this latter location, the artery is susceptible to blunt perineal trauma. The internal pudendal artery terminates as it supples the inferior rectal and perineal artery, which supplies the labia. The common clitoral artery continues to the clitoris. This artery bifurcates into a dorsal clitoral artery and a cavernosal clitoral artery.
Based upon animal research, it has been found that central nervous system areas primarily implicated in sexual arousal include the medial pre-optic, anterior hypothalamic region and related limbic-hippocampal structures of the brain.
Female sexual dysfunction which has its origin in abnormal arterial circulation into the vagina or clitoris during sexual stimulation may be considered a disorder of arousal. This vasculogenic female sexual dysfunction may include such clinical symptoms as delayed vaginal engorgement, diminished vaginal lubrication, pain or discomfort with intercourse (dyspareunia), diminished vaginal sensation, diminished vaginal orgasm, diminished clitoral sensation or diminished clitoral orgasm.
Moreover, traumatic injury to the ilio-hypogastric-pudendal arterial bed from pelvic fractures-or blunt perineal trauma may also result in diminished vaginal/clitoral blood flow following sexual stimulation and fall into the vasculogenic dysfunction category.
Vaginal pain may derive from a general vaginal hyperalgesia or sensitivity to stimulation associated with coitus (dyspareunia) when there has been sufficient genital engorgement and lubrication.
Treatment of female sexual dysfunction is gradually evolving as more clinical and basic science studies are dedicated to the investigation of this medical problem. Female sexual complaints are not all psychological in pathophysiology, especially for those individuals who may have a component of vasculogenic dysfunction contributing to the overall female sexual complaint. Aside from hormone replacement therapy, medical management of female sexual dysfunction remains in the early phases of development. All non-hormonal medications listed below are undergoing safety and efficacy testing for the treatment of male erectile dysfunction and are only in the experimental stage for the treatment of female sexual dysfunction.
Estrogen replacement therapy is presently used in post-menopausal women (either spontaneous or surgical) for the treatment of hot flashes, prevention of osteoporosis, and diminishment of the risk of heart disease. Estrogen replacement results in improved clitoral sensitivity, increased libido and decreased pain/burning during intercourse. Local or topical estrogen application relieves symptoms of vaginal dryness, burning, urinary frequency and urgency. No clinical evidence exists thus far that the use of topical estrogen cream results in relief of sexual complaints other than local vaginal pain or vaginal dryness.
Methyl testosterone may be used in combination with estrogen in post-menopausal women for symptoms of inhibited desire, dyspareunia or lack of vaginal lubrication. Topical vaginal testosterone is used for treatment of vaginal lichen planus. These women, usually elderly, are noted to have clitoral enlargement, increased facial hair and increased sexual appetite. There are conflicting reports regarding the benefit of methyl testosterone for the treatment of inhibited desire and/or vaginismus in pre-menopausal women.
In men, topical application of prostaglandin E1 combined with a skin enhancer such as SEPA is presently demonstrating initial success in pilot Phase II clinical trials. Clinical studies are necessary to determine the safety and efficacy of this medication used as a topically-administered vaginal vasoactive agent in the treatment of vasculogenic female dysfunction. However, one study has demonstrated increased clitoral blood flow and clitoral erection following local prostaglandin E1 injection into clitoral corporal erectile tissues.
Sildenafil functions as a selective type 5 (i.e. c-GMP specific) phosphodiesterase inhibitor, and acts to decrease the metabolism of c-GMP, the second messenger in nitric oxide mediated male erectile response. An oral formulation of this medication has proven to be safe and effective in improving erectile duration and rigidity. In females, nitric oxide/NOS exists in human vaginal and clitoral tissue. Sildenafil may prove useful alone, or possibly in combination with other vasoactive agents for the treatment of vasculogenic female sexual dysfunction. Clinical studies evaluating the efficacy of this medication in women are needed.
Phentolamine is currently available as an oral preparation with rapid absorption and metabolism. Phentolamine""s mechanism of action inducing vascular smooth muscle relaxation occurs via alpha-adrenergic blockade as well as by direct smooth muscle relaxation. Studies are currently in progress using this medication in women with female sexual dysfunction.
Despite these advances in the discovery of agents effective to treat female sexual dysfunction, there still exists a need for the discovery of additional compounds useful in the treatment of this condition.
In one embodiment, the present invention provides a method of treating or ameliorating sexual dysfunction in female mammals by administering to a mammal in need of such treatment a therapeutically effective amount of a compound which acts upon mid-brain pathways to increase blood flow to the ilio-hypogastric-pudendal arterial bed and genitalia.
In another embodiment, the present invention provides a method of combating vaginal pain by administering to a mammal in need of such treatment a therapeutically effective amount of a compound which acts upon mid-brain pathways to stimulate peripheral nerve release of nitric oxide (NO) in the pelvic nerve network, preferably from non-adrenergic, non-cholinergic (NANC) nerves. The vaginal pain may be general hyperalgesia (non-specific increased vaginal sensitivity) or pain associated with intercourse (dyspareunia).
The selected compound is one which acts upon any of the mid-brain pathways which include the dopaminergic, serotonergic, oxytocinergic or nitroxidergic mid-brain pathways.
In another embodiment, the present invention provides a method for producing an effective vasocongestive arousal in a female comprising administering a therapeutically effective amount of a compound which acts upon a mid-brain dopaminergic, serotonergic, oxytocinergic or nitroxidergic pathway to increase blood flow to the ilio-hypogastric-pudendal arterial bed and genitalia. By effective vasocongestive arousal is meant clitoral erection, vaginal and labialar engorgement, and lubrication adequate for intercourse.
In yet another embodiment, the present invention provides a means of treating vaginal engorgement insufficiency in a female mammal comprising administering a therapeutically effective amount of a compound which acts upon a mid-brain dopaminergic, serotonergic, oxytocinergic or nitroxidergic pathway to increase blood flow to the ilio-hypogastric-pudendal arterial bed and genitalia.
In another embodiment, the present invention provides a method of treating clitoral erectile insufficiency in a female mammal comprising administering a therapeutically effective amount of a compound which acts upon a mid-brain dopaminergic, serotonergic, oxytocinergic or nitroxidergic pathway to increase blood flow to the ilio-hypogastric-pudendal arterial bed and genitalia.
In still another embodiment, the present invention comprises a method of treating dyspareunia in a female mammal comprising administering a therapeutically effective amount of a compound which acts upon a mid-brain dopaminergic, serotonergic, oxytocinergic or nitroxidergic pathway to facilitate peripheral nerve release of NO in the pelvic nerve network, preferably from non-adrenergic, non-cholinergic nerves.
In the embodiments described above, an androgen may optionally be co-administered with the primary active compound, wherein co-administration of the androgen enhances or potentiates the effect of the principal therapeutic agent.
In yet another embodiment, the present invention provides a means of diagnosing the presence or absence of sexual dysfunction in a female mammal. The diagnostic method comprises the steps of administering apomorphine alone or in combination with an androgen and observing any change in physiologic response associated with sexual activity. A change indicates the presence of sexual dysfunction.
In the Drawing:
FIG. 1 is a histogram depicting yawning response of female test animals following administration, in a first study, of various doses of apomorphine.
FIG. 2 is a histogram depicting yawning response of female test animals administered, in a-second study, equal 80 microgram/kg doses of apomorphine at various times following the pre-administration of equal 480 microgram/kg doses of testosterone.
FIG. 3 is a graph showing blood levels of estrogen and progesterone in the female rat during various stages of the rat estrous cycle.
FIG. 4 is a histogram depicting genital licking and yawn response data from a third study in which female rats were administered either saline or 80 micrograms/kg of apomorphine during either the proestrus/estrus or metestrus/diestrus stages of the estrous cycle.
FIG. 5 presents histograms depicting genital licking and yawn response data from a fourth study in which female rats were pre-administered 480 microgram/kg doses of testosterone 36 hours prior to the administration of saline or apomorphine during a particular stage of the estrous cycle. The data compare responses in the proestrus/estrus and the metestrus/diestrus stages following administration of testosterone and either saline or apomorphine.
FIGS. 6 and 7 are histograms showing genital lick and yawn response data, respectively, from a study in which female rats were administered either saline or apomorphine, with or without the prior administration of testosterone. Data are presented for both the proestrus/estrus and metestrus/diestrus stages of the estrous cycle.
FIG. 8 is a histogram comparing genital lick and yawn response data which compare the data from the studies where either saline or an 80 microgram/kg dose of apomorphine was administered to test animals with and without prior administration of a 480 microgram/kg dose of testosterone.
FIGS. 9 and 10 are histograms presenting genital lick and yawn response data, respectively, comparing intact animals administered control or saline during the metestrus/diestrus stage of the rat estrous cycle with ovariectomized animals administered a corresponding regimen of drug or control.